RuCl2(dmso)4 catalyzes the solvent-free indirect Friedlaender synthesis of polysubstituted quinolines from alcohols

Article abstract of DOI:10.1002/ejoc.200600945

The first synthesis of polysubstituted quinoline derivatives from aromatic or aliphatic alcohols with RuCl₂(dmso)₄ as catalyst under solvent-free conditions is described. The reaction involves the in situ oxidation of alcohols to the

Full text of DOI:10.1002/ejoc.200600945

FULL PAPER
DOI: 10.1002/ejoc.200600945
RuCl (dmso) Catalyzes the Solvent-Free Indirect Friedländer Synthesis of
2
4
Polysubstituted Quinolines from Alcohols
[a]
[a]
[a]
Ricardo Martínez, Diego J. Ramón,* and Miguel Yus*
Keywords: Annulation / Homogeneous catalysis / Hydrogen transfer / Ruthenium / Synthetic methods
The first synthesis of polysubstituted quinoline derivatives
by a Friedländer annulation process. The whole process is a
from aromatic or aliphatic alcohols with RuCl (dmso) as cat- mild, efficient, selective, and high-yielding single-step pro-
2
4
alyst under solvent-free conditions is described. The reaction
involves the in situ oxidation of alcohols to the corresponding
carbonyl compounds through a hydrogen-transfer, followed
cedure.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
storage and stability of carbonyl reagents. Moreover, this
reaction is usually carried out in polar solvents, resulting in
tedious workup procedures.
The presence of quinoline scaffolds in the frameworks of
various pharmacologically active compounds, as well as in
various natural products, has spurred on the development
[
1]
of many different methodologies for their synthesis.
Among their different applications,[ functionalized quino-
2]
lines are in widespread use as a result of their anti-malar-
ial,[ anti-inflammatory,
3]
[4]
anti-asthmatic,
[5]
anti-bacte-
rial, and anti-hypersensitive activities.[7] Several different
strategies for the preparation of substituted quinolines are
known, with the Friedländer annulation being the most
simple, straightforward, and widely used approach
[6]
Scheme 1. Friedländer annulation.
[
8]
(
Scheme 1). This type of reaction is usually performed
A new methodology using 2-aminobenzyl alcohol as
source of electrophilic partner 1 in the Friedländer annu-
lation has recently been proposed as an alternative, and
some of the problems mentioned above, such as the instabil-
ity of the corresponding aminobenzaldehyde, have been
overcome in this way. The reaction is initiated by hydride
abstraction from the benzyl alcohol by the catalysts, fol-
lowed by imine formation and a final aldol-ring closing pro-
cess under basic conditions. Different metal complexes have
been proposed as catalysts: they include Grubbs’ ruthenium
either by heating an aqueous or alcoholic solution of reac-
tants at reflux in the presence of base, or by heating the
above reagents at high temperature (up to 250 °C) in the
absence of catalyst. 2-Aminophenyl ketone or aldehyde de-
rivatives 1 are used as the electrophilic partner and different
carbonyl compounds possessing acidic α-hydrogen atoms 2
are employed as source of the nucleophile. Under thermal
or base catalysis conditions, however, aminobenzophenone
1
2
(
2
1a: R = H, R = Ph) failed to react with simple ketones
[9]
.
This limitation has been overcome, though, by the use
[12]
[13]
complexes,
ruthenium-grafted hydrotalcite,
RuCl2-
[10]
of acid catalysts such as Brønsted acids (polyphosphoric,
sulfamic, or p-toluenesulfonic acid) or Lewis acids
[14]
[15]
[16]
(dmso)4,
RhCl(PPh3)3,
and CuCl2.
palladium on charcoal,
It is not only the carbonyl
[
11]
[17]
[18]
[IrCl(cod)]2
[
AuCl , Y(OTf) , ZnCl , Ag PW O , FeCl , or Mg-
1
2
3
3
2
3
12 40
3
electrophilic partner 2-aminobenzaldehyde (1a: R = R =
H) that can be substituted by the corresponding benzyl
alcohol by this approach: ketones 2 can also be substituted
(
ClO ) ]. Nevertheless, most of the synthetic approached re-
4 2
ported so far suffer from the need for high temperatures or
harsh reaction conditions, low yields, use of hazardous and
often expensive catalysts, and problems associated with the
[19]
by the corresponding secondary alcohols. Here we report
the expansion of this indirect approach to the Friedländer
annulation not only with synthetic equivalents of simple 2-
aminobenzaldehyde but also with more challenging
[
a] Instituto de Síntesis Orgánica (ISO) and Departamento de
Química Orgánica, Facultad de Ciencias, Universidad de Al-
icante,
systems such as 2-aminobenzophenone derivatives. The
Apdo. 99, 03080 Alicante, Spain
Fax: +34-965-903549
E-mail: djramon@ua.es
yus@ua.es
[20]
RuCl (dmso)4
complex was chosen as catalyst, since it
2
has shown excellent activity both as a hydrogen-transfer
[
21]
catalyst (needed for the first stage of the process) and as
Eur. J. Org. Chem. 2007, 1599–1605
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1599

R. Martínez, D. J. Ramón, M. Yus
FULL PAPER
a Lewis acid[22] (needed for the annulation process with 2-
aminobenzophenone derivatives), with both activities being
very important for the success of the whole process.
Results and Discussion
We began our study by optimizing the reaction condi-
tions between 2-aminobenzophenone (1b) and 1-phenyl-
ethanol (4a) to give the corresponding quinoline 3a
(Table 1). The initial reaction conditions gave the expected
product with a modest yield (Table 1, Entry 1), but it
should be pointed out that, although the yield was not very
high, this is the first 4-phenylquinoline synthesis by an indi-
rect Friedländer approach and that the modest yield could
be due to difficulty in the re-oxidation of the ruthenium
hydride formed in situ (see mechanistic considerations be-
low in Scheme 2). Under these conditions, this re-oxidation
could be performed either by the reaction of ruthenium hy-
[23]
dride formed in situ with oxygen, or by the direct forma-
tion of molecular hydrogen.[ The presence of an organic
scavenger of hydrogen such as benzophenone or the ad-
dition of an extra amount of alcohol 4a had a small influ-
ence on the result (Table 1, Entries 2 and 3), but the re-
moval of the solvent had a great impact (Table 1, Entries 4
and 5), with the reaction giving an excellent chemical yield
under solvent-free conditions.[ It is notable that these
conditions also offer several other advantages, such as,
among others, ease of workup and the low amount of en-
ergy used in the heating. While a doubling of the amount
of base produced a marginal increase in the yield (Table 1,
Entry 6), any reduction in the amount of base or change
in the nature of the hydrogen scavenger had an important
24]
25]
Scheme 2. Proposed catalytic indirect Friedländer annulation pro-
detrimental effect (Table 1, Entries 7 and 8). The nature of cess.
Table 1. Optimization process.
Entry
Solvent
Base [mol-%]
T [°C]
Hydrogen scavenger [mol-%]
Yield[a] [%]
1
2
1,4-dioxane
1,4-dioxane
1,4-dioxane
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
KOH [100]
KOH [100]
KOH [100]
KOH [100]
KOH [100]
KOH [200]
KOH [10]
100
100
100
100
100
100
100
100
100
100
100
100
60
–
47
57
53
92
80
94
15
76
0
benzophenone [100]
benzophenone [100]
benzophenone [100]
benzophenone [100]
benzophenone [100]
benzophenone [100]
dodec-1-ene [100]
benzophenone [100]
benzophenone [100]
benzophenone [100]
benzophenone [100]
benzophenone [100]
benzophenone [100]
[
b]
c]
3
4
5
6
7
8
9
1
1
1
1
1
[
KOH [100]
Na
2
CO
4
3
[100]
[100]
0
1
2
3
4
K
3
PO
0
KOtBu [100]
KOtBu [100]
KOtBu [100]
KOtBu [100]
99
94
89
93
[
[
c]
c]
140
[
a] Isolated yields after acidic-basic aqueous extraction. [b] Two equivalents of alcohol 4a were used. [c] Yield obtained after 24 h reaction
time.
1600
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1599–1605

Ru-Catalyzed Solvent-Free Friedländer Synthesis of Quinolines
FULL PAPER
the base also had an important role: the reaction failed with in cases in which primary alcohols such as 2-phenylethanol
bases weaker than KOH, such as Na CO or K PO , while (4h) were used, this result show the versatility of this ap-
2
3
3
4
the use of slightly stronger bases such as potassium tert- proach (Table 2, Entry 8).
butoxide gave the expected product in practically quantita-
The reaction worked not only with 1-substituted ethanols
tive yield (compare Entries 4 and 9–11 in Table 1). Under but also with other alcohols with longer chains, in these
these conditions, reduction of the reaction time gave slightly cases yielding the corresponding 3-substituted quinolines
poorer results (Table 1, Entry 13). We finally studied the in- (Table 2, Entries 9–11).
fluence of temperature, finding that lower or higher tem-
peratures gave worse or similar results, respectively (com- methoxy derivative 1c did not have any important conse-
pare Entries 11–14 in Table 1). quence, the reaction with 2-aminoacetophenone (1d) pro-
While the change of 2-aminobenzophenone (1b) for its
Once the best reaction conditions had been found duced a notable diminution of the chemical yield (compare
(Table 1, Entry 11), other 2-aminophenyl ketone derivatives Entries 1, 12 and 13 in Table 2). The presence of halogen
1, as well as alcohols 4, were tested (Table 2). The reaction atoms on the aromatic ring of the ketone 1 did not have
gave practically quantitative yields not only with 1-phenyl- any appreciable effect on the chemical yields (Table 2, En-
ethanol (4a) but also for other related 4-substituted phenyl tries 14–19). The reaction between 2,5-diaminobenzophe-
alcohols (Table 2, Entries 1–3) independently of the elec- none (1f) and the alcohol 4a merits a separate comment,
tronic natures of the substituents (electron-donating group since the presence of two amino functionalities might have
in the methyl derivative 4b or electron-withdrawing one in had a detrimental effect on the yield. However, the reaction
the trifluoromethyl derivative 4c). Yields were also good for gave the expected 6-aminoquinoline product 3t as the only
the sterically hindered 1-(2-naphthyl)ethanol (4d) and for isolated product, this result indicating that the condensation
the acid sensitive 1-(2-furyl)ethanol (4e) (Table 2, Entries 4 of the amino group with the ketone formed in situ is essen-
and 5, respectively). The reaction also worked well for ali- tially reversible under these reaction conditions (see
phatic alcohols such as 3,3-dimethylbutan-2-ol (4f; Table 2, Scheme 2), since it should have occurred prior to the aldol
Entry 6). Pleasingly, the reaction was regioselective in the condensation.
case of heptan-2-ol, giving only one of the two possible
Once we had found that the substitution of the nucleo-
quinoline isomers (Table 2, Entry 7), the aldol condensation philic carbonyl partner by the corresponding alcohol in the
taking place at the methyl position of the alcohol 4g rather Friedländer annulation could be achieved in a RuCl2-
than at the methylenic one. Although the yields were lower (dmso) -catalysed process, we focused our attention on the
4
Table 2. Indirect Friedländer annulation with aminophenyl ketones 1 and alcohols 4.
Entry
Ketone
Alcohol
Product
R1
R2
R3
R4
Yield[a] [%]
b]
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1d
1e
1e
1e
1e
1e
1e
1f
4a
4b
4c
4d
4e
4f
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOC
Me
Ph
Ph
Ph
Ph
4-MeC
4-CF
2-naphthyl
2-furyl
tBu
CH
H
Ph
–(CH
H
H
H
H
H
H
H
Ph
Me
99[
96[
99
b]
6
C
H
4
3
6
H
4
78
85
83[
95
b]
4g
4h
4i
3
(CH
2
)
4
51[
94[
b]
b]
10
11
12
13
14
15
16
17
18
19
20
4j
3j
3k
3l
2
)
4
–
81
4k
4a
4a
4a
4c
4f
–[1,2-C
Ph
Ph
6
H
4
(CH
2
)
2
]–
H
H
H
H
H
H
H
H
H
88
91
48
98
97
79
65
79
75
65
6 4
H
3m
3n
3o
3p
3q
3r
3s
3t
H
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-NH
Ph
4-CF
tBu
Ph
Ph
4-CF
Ph
3
C
6
H
4
4a
4a
4f
6 4
2-FC H
2-ClC
2-ClC
Ph
6
H
H
4
6
4
3
C
6
H
4
4a
2
[a] Isolated yields after column chromatography (silica gel: hexane/ethyl acetate). [b] Obtained yield after acidic-basic aqueous extraction.
Eur. J. Org. Chem. 2007, 1599–1605
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1601

R. Martínez, D. J. Ramón, M. Yus
FULL PAPER
substitution of the electrophilic carbonyl partner 1 of the to force the formation of the corresponding potassium alk-
reaction by the related alcohol 5 (Table 3). Treatment of the oxide 6 and/or 7, which are the real substrates for the hy-
ketone 2 with the alcohol 5 in the presence of potassium dride abstraction. The ruthenium catalytic species [Ru],
tert-butoxide under solvent-free conditions thus gave the ex- which is not necessarily the starting ruthenium complex,
pected quinolines 3 with results similar to those obtained reacts with the alkoxide to yield the corresponding carbonyl
previously, indicating that the replacement of the ketone 1 compounds 1 and 3, and a ruthenium hydride intermediate,
by its alcohol derivative is also possible.
which is re-oxidized by reaction with benzophenone. Other
possible routes for ruthenium re-oxidation might also com-
pete with the reported main pathway. The condensation of
the two carbonyl compounds 1 and 3 yields the imine deriv-
ative 8, which gives rise to the corresponding polysubsti-
tuted quinoline through a Lewis acid-catalyzed process, ac-
cording to the previously mentioned literature.
Table 3. Indirect Friedländer annulation with the alcohol 5 and
ketones 2.
Conclusions
Entry Ketone
Product R1
R2
Yield[a]
%]
This study represents the first example of an indirect
Friedländer synthesis of 4-substituted or 4,6-disubstituted
quinolines with the use of alcohols as reagents. This tech-
nique has several advantages, such as the ease of workup
and product purification, the absence of solvents and strong
acid catalysts, and the ease of storage of reagents. The reac-
tion is catalyzed efficiently by RuCl (dmso) , giving the cor-
[
1
2
3
2a
2b
2c
3a
3b
3k
Ph
4-MeC H
6 4
–[1,2-C H (CH ) ]–
6 4 2 2
H
H
64
73[
85
b]
[
a] Isolated yields after acidic-basic aqueous extraction. [b] Ob-
tained yield after column chromatography (silica gel: hexane/ethyl
acetate).
2
4
responding quinoline derivatives in good to excellent yields.
The yields are practically independent either of the nature
of the alcohol used (aromatic or aliphatic) or of its substitu-
tion (primary or secondary alcohols). The catalyst used is
very cheap, stable and easy to handle and to prepare. The
reaction is regioselective with regard to the carbonyl com-
ponent formed in situ, taking place at its less substituted
position.
Finally we studied the possible double replacement of
both the nucleophilic and the electrophilic components in
this process (Table 4). Thus, treatment of the alcohol 4
(source of the nucleophilic carbonyl partner in the classical
procedure) with the amino alcohol 5 (source of the electro-
philic carbonyl partner) gave results similar to those ob-
tained previously on changing only one of the two compo-
nents of the reaction. In these cases it needs to be taken in
account that, although the amount of catalyst is the same
as in previous cases, the real equivalents are halved, owing Experimental Section
to the presence of two equivalents of alcohols to be oxid-
General Remarks: Full general statements have been detailed else-
ized. In addition, it is remarkable that the yield for the pri-
mary alcohol was lower than for secondary ones (compare
Entries 1, 2 and 4 with Entry 3 in Table 4).
where.[ Ketone 1c was prepared in 81% overall yield by treat-
ment of isatoic anhydride with N,O-dimethylhydroxylamine hydro-
chloride in aqueous ethanol to give the corresponding 2-amino-
benzamide, which then was treated with 4-methoxyphenyllithium
obtained in situ from butyllithium and 4-bromoanisole by literature
26]
[27]
Table 4. Indirect Friedländer annulation with alcohols 4 and 5.
procedures.[ Alcohol 5 was prepared in 87% yield by standard
28]
[29]
[
30]
reduction of the ketone 1b with NaBH
RuCl (dmso) complex was prepared in excellent yields (85–99%)
by brief heating of RuCl
4
in ethanol.
The
2
4
[
31]
3
2
·3H O at reflux in dimethyl sulfoxide.
Other reagents were commercially available (Acros, Aldrich, Strem)
and were used as received. Solvents were dried by standard pro-
cedures.[
32]
Entry Alcohol Product
R1
R2
Yield[a]
%]
General Procedure for the Indirect Friedländer Annulation: The cor-
responding alcohol 4 or ketone 2 (2 mmol) and potassium tert-
butoxide (0.24 g, 2 mmol) were added to a mixture of RuCl2-
[
1
2
3
4
4a
4b
4h
4j
3a
3b
3h
3j
Ph
4-MeC
H
H
H
Ph
72
87
43
92
6
H
4
(
4
dmso) (0.02 g, 0.02 mmol) and the corresponding 2-aminophenyl
ketone or alcohol derivative (1 or 5, 2 mmol). The resulting mixture
was heated at 100 °C with stirring for 48 h. The reaction mixture
was then allowed to cool to room temperature and quenched by
2 4
–(CH ) –
[a] Isolated yields after acidic-basic aqueous extraction.
4
the successive addition of a saturated solution of NH Cl (10 mL)
and ethyl acetate (10 mL). The mixture was filtered off through
Finally, the possible catalytic cycle merits a separate
comment (Scheme 2). According to our previous proposed
celite and extracted with acetate (3ϫ10 mL). The combined or-
catalytic cycle for the related process,[14b] we had supposed ganic layers were dried with anhydrous Na SO , filtered and con-
2
4
that the necessity to use stoichiometric amounts of base is centrated (15 Torr) to give a residue, which was purified by column
1
602 Eur. J. Org. Chem. 2007, 1599–1605
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Ru-Catalyzed Solvent-Free Friedländer Synthesis of Quinolines
FULL PAPER
chromatography on silica gel with suitable mixtures of hexane/ethyl
acetate. Alternatively (see Tables 1 to Table 4), the resulting residue
was dissolved in ethyl acetate (10 mL) and extracted with hydro-
chloric acid (2 , 3ϫ10 mL). The resulting aqueous solution was
subsequently basified with a solution of NaOH (3 ) until pH 13,
producing a suspension, which was finally extracted with acetate
3066, 1592, 1545 cm–1 (C=CH). MS: m/z (%) = 272 (20) [M + 1]+,
271 (100), 270 (23), 243 (16), 242 (15), 241 (24).
2
-(tert-Butyl)-4-phenylquinoline (3f):[33] White solid (0.43 g, 83%),
1
m.p. 79–80 °C. t
r
= 16.8. R
f
= 0.79 (hexane/ethyl acetate 4:1). H
NMR: δ = 1.49 [s, 9 H, C(CH
3
)
3
], 7.35–7.40, 7.60–7.65, 7.83 and
8
.12 (2ϫm and 2ϫd, respectively, J = 8.4 and 8.4 Hz, 1 H each,
), 7.40–7.50 (m, 6 H, Ph and quinoline H ) ppm.
C NMR: δ = 30.15 (3 C), 38.10, 118.40 (2 C), 124.95, 125.30,
(3ϫ10 mL), and the combined organic layers were dried with an-
5
,6,7,8
3
quinoline H
hydrous Na SO , filtered and concentrated (15 Torr) to afford the
2
4
1
3
pure quinoline 5. Yields are included in Tables 1 to 4. Physical and
spectroscopic data follow, together with literature references for
known compounds.
1
1
25.60, 128.10, 128.45, 128.80, 129.55 (2 C), 129.75, 138.80, 147.90,
–
1
48.10, 168.70 ppm. IR (film): ν˜ = 3062, 1596, 1571, 1554 cm
+
(C=CH). MS: m/z (%) = 261 (36) [M] , 260 (29), 247 (20), 246
2
,4-Diphenylquinoline (3a):[33] Colorless solid (0.56 g, 99%), m.p. (100), 219 (47), 205 (14), 204 (20).
1
r f
111–113 °C. t = 20.7. R = 0.60 (hexane/ethyl acetate 4:1). H
2
R
1
-Pentyl-4-phenylquinoline (3g): White oil (0.52 g, 95%), t
r
= 17.6.
= 0.56 (hexane/ethyl acetate 4:1). H NMR: δ = 0.85–0.95, 1.35–
.45, 1.80–1.90 and 2.95–3.00 [4ϫm, 3, 4, 2 and 2 H, respectively,
NMR: δ = 7.43–7.55, 7.70–7.75, 7.80, 7.85–7.90 and 8.15–8.25
2ϫm, s and 2ϫm, respectively, 9, 1, 1, 1 and 3 H, respectively,
1
f
(
13
ArH) ppm. C NMR: δ = 119.30, 125.55, 125.70, 126.30, 127.55
2 C), 128.35, 128.55 (2 C), 128.80 (2 C), 129.30, 129.45, 129.50 (2
C), 130.10, 138.35, 139.60, 148.75, 149.10, 156.85 ppm. IR (KBr):
3
(CH
2
)
4
CH
3
], 7.22 (s, 1 H, quinoline H ), 7.45–7.50 (m, 5 H, Ph),
(
7
.35–7.45, 7.60–7.65, 7.84 and 8.12 (2ϫm and 2ϫd, respectively,
5
,6,7,8
13
J = 8.3 and 8.3 Hz, 1 H each, quinoline H
) ppm. C NMR:
–1
ν˜ = 3055, 1597, 1496, 1402 cm (C=CH). MS: m/z (%) = 281 (69)
δ = 13.90, 22.45, 29.65, 31.70, 39.20, 121.40, 125.10, 125.45, 125.55,
+
[
M] , 280 (100), 202 (11).
1
1
28.10, 128.35 (2 C), 129.00, 129.10, 129.35 (2 C), 138.15, 148.30,
2
-(4-Methylphenyl)-4-phenylquinoline (3b):[33] Colorless oil (0.57 g,
–1
48.35, 162.45 ppm. IR (film): ν˜ = 3063, 1584, 1549 cm (C=CH).
1
99%), t
r
= 22.7. R
f
= 0.65 (hexane/ethyl acetate 4:1). H NMR: δ
+
MS: m/z (%) = 275 (2) [M] , 246 (12), 232 (20), 220 (18), 219 (100).
=
2.39 (s, 3 H, CH
3
), 7.29 and 8.08 (2ϫd, J = 8 and 8 Hz, 2 H
), 7.40–7.45, 7.65–7.70, 7.75, 7.85 and 8.21 (2ϫm,
HRMS calcd. for C20
H
21N: 275.1674; found: 275.1675.
,4-Diphenylquinoline (3h):[35] Pale yellow solid (0.29 g, 51%), t
=
r
each, C
6
H
4
CH
3
3
s and 2ϫd, respectively, J = 8 and 8 Hz, 1 H each, quinoline
1
3,5,6,7,8
13
f
19.9. R = 0.45 (hexane/ethyl acetate 4:1). H NMR: δ = 7.15–7.25,
H
1
(
), 7.45–7.55 (m, 5 H, Ph) ppm. C NMR: δ = 21.25,
19.10 (2 C), 125.50, 125.60, 126.05, 127.35 (2 C), 128.25, 128.45
2 C), 129.35, 129.50 (2 C), 129.95 (2 C), 136.75, 138.40, 139.30,
7
.30–7.35, 7.45–7.50 and 7.70–7.75 (4 m, 7, 3, 1 and 2 H, respec-
8
tively, ArH), 8.19 (d, J = 8.2 Hz, 1 H, quinoline H ), 9.00 (s, 1 H,
quinoline H ) ppm. C NMR: δ = 126.55, 126.85, 127.00 (2 C),
2
13
1
1
48.75, 148.95, 156.70 ppm. IR (film): ν˜ = 3055, 1591, 1542,
492 cm–1 (C=CH). MS: m/z (%) = 295 (73) [M]+, 294 (100), 202
127.20, 127.70, 128.05, 128.10 (2 C), 129.05, 129.45, 130.10 (2 C),
1
30.50 (2 C), 133.10, 136.25, 138.10, 145.45, 147.50, 151.75 ppm.
(
10).
-Phenyl-2-(4-trifluoromethylphenyl)quinoline (3c): Colorless solid
0.68 g, 99%), m.p. 76–78 °C. t = 20.1. R = 0.71 (hexane/ethyl
acetate 4:1). H NMR: δ = 7.40–7.45, 7.65–7.75, 7.85 and 8.20–
–
1
IR (film): ν˜ = 3063, 1560, 1501 cm (C=CH). MS: m/z (%) = 282
4
+
(
(
21) [M + 1] , 281 (100), 280 (63), 278 (12), 266 (11), 252 (17), 139
11).
(
r
f
1
3
-Methyl-2,4-diphenylquinoline (3i): Pale yellow solid (0.55 g, 94%),
8
3
2
.25 (2ϫm, dd and m, respectively, J = 0.9 and 8.4 Hz, 6, 4, 1 and
1
H, respectively, ArH) ppm. C NMR: δ = 124.20 (q, F
1
3
m.p. 131–133 °C. t = 22.4. R = 0.57 (hexane/ethyl acetate 4/1). H
1,2
J =
r
f
NMR: δ = 2.59 (s, 3 H, CH
3
), 7.75 and 7.80–8.10 (d and m, respec-
72.2 Hz, CF ), 125.5–125.65 (m, 3 C), 125.90, 126.75, 127.70, (2
3
tively, J = 6.9 Hz, 2 and 11 H, respectively, 2ϫPh and quinoline
C), 128.50, 128.55 (2 C), 129.45 (2 C), 129.70, 130.20, 130.95 (q,
5
,6,7
8
13
F
H
), 8.62 (d, J = 8.3 Hz, 1 H, quinoline H ) ppm. C NMR: δ
J
1,3
=
32.9 Hz, CCF
3
), 138.05, 142.75, 148.70, 149.45,
–1
= 18.50, 125.90, 126.15, 126.65, 127.00, 127.75, 128.00, 128.25 (2
C), 128.45, 128.55 (2 C), 128.85 (2 C), 129.25 (2 C), 129.40, 137.65,
1
54.95 ppm. IR (KBr): ν˜ = 3069, 1625, 1585, 1555 cm (C=CH).
+
MS: m/z (%) = 350 (14) [M + 1] , 349 (69), 348 (100), 202 (100).
HRMS calcd. for C22 N: 349.1078; found: 349.1054.
1
1
41.50, 146.20, 147.70, 160.75 ppm. IR (film): ν˜ = 3058, 1617, 1575,
14 3
H F
–
1
+
554 cm (C=CH). MS: m/z (%) = 295 (40) [M] , 294 (100).
17N: 295.1361; found: 295.1357.
2
-(Naphthalen-2-yl)-4-phenylquinoline (3d):[34] Pale yellow oil
HRMS calcd. for C22
H
1
(0.52 g, 78%), t
r
= 32.1. R
f
= 0.67 (hexane/ethyl acetate 4:1). H
NMR: δ = 7.45–7.60 (m, 9 H, ArH), 7.65 (s, 1 H, quinoline H ), 9-Phenyl-1,2,3,4-tetrahydroacridine (3j):[36] Pale yellow solid (0.48 g,
3
7
8
8
1
1
.65–7.80 and 7.90–7.95 (2ϫm, 2 H each, ArH), 8.00 (d, J =
r f
92%), m.p. 136–138 °C. t = 17.9. R = 0.69 (hexane/ethyl acetate
4:1). H NMR: δ = 1.75–1.85, 1.95–2.00, 2.60 and 3.18 [2ϫm and
2ϫt, respectively, J = 6.7 and 7 Hz, respectively, 2 H each,
5
1
.4 Hz, 1 H, quinoline H ), 8.20–8.25 (m, 1 H, ArH), 8.30 (d, J =
8
13
.4 Hz, 1 H, quinoline H ) ppm. C NMR: δ = 123.40, 125.35,
25.50, 125.65, 125.70, 125.90, 126.60, 127.80, 128.35, 128.40,
28.55 (2 C), 129.10, 129.55, 129.60 (2 C), 130.10, 131.25, 134.00 J = 8.0 Hz, 4, 4 and 1 H, respectively, ArH) ppm. C NMR: δ =
2 4
(CH ) ], 7.20–7.30, 7.40–7.60 and 7.98 (2ϫm and d, respectively,
1
3
(2 C), 138.05, 138.65, 148.65 (2 C), 158.95 ppm. IR (film): ν˜ =
22.85, 23.00, 28.00, 34.20, 125.30, 125.75, 126.60, 127.65, 128.25,
–1
3
+
054, 1585, 1541, 1492 cm (C=CH). MS: m/z (%) = 332 (13) [M
128.30, 128.55 (2 C), 129.05 (2 C), 137.10 (2 C), 146.25, 146.40,
+
–1
1] , 331 (63), 330 (100), 328 (20), 254 (45), 164 (16).
159.00 ppm. IR (film): ν˜ = 3060, 1571, 1495 cm (C=CH). MS:
+
m/z (%) = 259 (100) [M] , 230 (12), 183 (10).
2
-(Furan-2-yl)-4-phenylquinoline (3e):[33] Yellow oil (0.56 g, 85%), t
r
=
20.1. R
f
= 0.56 (hexane/ethyl acetate 4:1). H NMR: δ = 6.59 7-Phenyl-5,6-dihydrobenzo[c]acridine (3k):[37] White solid (0.54 g,
1
and 7.23 (2ϫd, J = 1.4 and 3.4 Hz, respectively, 1 H each,
OCH=CHCH), 7.50–7.55 and 7.62 (m and s, respectively, 6 and 1
H, respectively, Ph and OCH=CH), 7.25–7.45, 7.70–7.75, 7.77, 7.85
and 8.19 (2ϫm, s and 2ϫd, J = 8.4 and 8.4 Hz, 1 H each, quino-
88%), m.p. 149–151 °C. t
4:1). H NMR: δ = 2.75–2.85 (m, 4 H, CH
r
= 28.2. R
f
= 0.67 (hexane/ethyl acetate
CH ), 7.15–7.30, 7.35–
1
2
2
7.50 and 7.55–7.60 (3 m, 5, 5 and 1 H, respectively, ArH), 8.16 and
8.62 (2ϫd, J = 8.4 and 7.6 Hz, respectively, 1 H each, quinoline
line H3
,5,6,7,8
) ppm. C NMR: δ = 110.15, 112.20, 117.70, 125.70,
25.80, 126.20, 128.45, 128.55 (2 C), 129.50 (2 C), 129.70, 129.75,
38.15, 144.10, 148.55, 148.65, 149.10, 153.75 ppm. IR (film): ν˜ =
13
H ) ppm. C NMR: δ = 26.40, 28.15, 125.80, 125.90, 126.30,
5,8
13
1
1
127.15, 127.60, 127.80, 127.95 (2 C), 128.35, 128.45 (2 C), 129.40
(2 C), 129.55 (2 C), 135.00, 136.85, 139.15, 145.20, 147.15,
Eur. J. Org. Chem. 2007, 1599–1605
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1603

R. Martínez, D. J. Ramón, M. Yus
FULL PAPER
1
53.00 ppm. IR (film): ν˜ = 3062, 1583, 1551 cm–1 (C=CH). MS:
m, 2, 5 and 2 H, respectively, ArH), 7.84 (s, 1 H, quinoline H ),
3
+
13
F
m/z (%) = 308 (23) [M + 1] , 307 (100), 306 (89), 305 (14), 304
8.15–8.20 (m, 3 H, ArH) ppm. C NMR: δ = 116.20 (d,
J
1,3
=
F
(26).
21.5 Hz), 120.85, 124.35 (d,
J
J1,3 = 18.8 Hz), 124.50, 125.05 (d,
F
1,4 = 16.2 Hz), 126.55, 127.45 (2 C), 128.80 (2 C), 129.55, 130.50,
30.80 (d, F 1,5 = 8.1 Hz), 131.55, 131.60 (d, F
1,4 = 14.8 Hz),
32.35, 138.95, 142.45, 146.95, 156.95, 159.55 (d,
49.3 Hz) ppm. IR (film): ν˜ = 3049, 1615, 1596, 1542 cm
4
-(4-Methoxyphenyl)-2-phenylquinoline (3l):[38] Pale yellow oil
1
1
2
J
J
1
(
0.57 g, 91%), t
NMR: δ = 3.85 (s, 3 H, OCH
and 2ϫm, respectively, J = 9.5 Hz, 2, 6 and 1 H, respectively, Ph
and C O), 7.77, 7.92, 8.15–8.20 and 8.22 (s, d, m and d, respec-
tively, J = 8.4 and 8.4 Hz, 1, 1, 2 and 1 H, respectively, quinoline
r
= 29.0. R
f
= 0.47 (hexane/ethyl acetate 4:1). H
F
J
1,2
=
3
), 7.05, 7.40–7.50 and 7.65–7.70 (d
–
1
+
(
3
C=CH). MS: m/z (%) = 335 (34) [M + 2] , 334 (49), 333 (100),
32 (92), 298 (33), 296 (13), 149 (15), 148 (13). HRMS calcd. for
13ClFN: 333.0721; found: 333.0731.
6
H
4
21
C H
3
,5,6,7,8
13
H
) ppm. C NMR: δ = 55.35, 114.00 (2 C), 119.25, 125.60,
1
1
25.90, 126.15, 127.50 (2 C), 128.75 (2 C), 129.20, 129.35, 130.05,
6-Chloro-4-(2-chlorophenyl)-2-phenylquinoline (3r): White needles
(0.55 g, 79%), m.p. 110–112 °C. t = 28.2. R = 0.62 (hexane/ethyl
). acetate 4:1). H NMR: δ = 7.35–7.65 (m, 9 H, ArH), 7.81 (s, 1 H,
3
30.60, 130.75 (2 C), 139.70, 148.80, 148.85, 156.85, 159.80 ppm.
r
f
–1
1
IR (film): ν˜ = 3060, 1613, 1553, 1508 (C=CH), 2836 cm (OCH
+
5
13
MS: m/z (%) = 312 (22) [M + 1] , 311 (100), 310 (84), 280 (28),
quinoline H ), 8.15–8.20 (m, 3 H, ArH) ppm. C NMR: δ =
267 (29).
120.50, 124.30, 12.45, 126.90, 127.50 (2 C), 128.83 (2 C), 129.60,
1
1
1
3
2
30.00, 130.55, 131.25, 131.65, 132.25, 133.20, 136.25, 138.95,
4
-Methyl-2-phenylquinoline (3m):[33] Pale yellow oil (0.21 g, 48%),
45.65, 146.85, 156.90 ppm. IR (film): ν˜ = 3067, 1606, 1592,
1
t
r
= 18.3. R
f
= 0.57 (hexane/ethyl acetate 4:1). H NMR: δ = 2.76
), 7.45–7.55, 7.70–7.75, 7.99 and 8.15–8.20 (2ϫm, d
–
1
+
546 cm (C=CH). MS: m/z (%) = 353 (11) [M + 4] , 352 (20),
51 (65), 350 (61), 349 (100), 348 (63), 316 (18), 315 (14), 314 (56),
78 (20), 277 (15), 201 (11), 139 (30), 125 (13). HRMS calcd. for
(s, 3 H, CH
3
and m, respectively, J = 8.4 Hz, 4, 2, 1 and 3 H, respectively,
ArH) ppm. 13C NMR: δ = 19.00, 119.75, 123.60, 126.00, 127.25,
C
21
H13Cl
2
N: 349.0425; found: 349.0421.
6-Chloro-4-(2-chlorophenyl)-2-(4-trifluoromethylphenyl)quinoline
(3s): White solid (0.62 g, 75%), m.p. 163–165 °C. t = 26.1. R
0.61 (hexane/ethyl acetate 4:1). H NMR: δ = 7.35–7.50, 7.60–7.70,
1
1
1
2
27.50 (2 C), 128.75 (2 C), 129.15, 129.30, 130.30, 139.80, 144.75,
48.10, 157.05 ppm. IR (film): ν˜ = 3060, 1602, 1547, 1514,
492 cm–1 (C=CH). MS: m/z (%) = 220 (17) [M + 1] , 219 (100),
18 (43), 217 (23), 205 (12), 204 (72), 108 (13).
+
r
f
=
1
7
.78, 7.84, 8.18 and 8.30 (2ϫm, d, s and 2ϫd, respectively, J =
6
9
4
-Chloro-2,4-diphenylquinoline (3n):[33] Colorless needles (0.62 g,
8
.2, 8.9 and 8 Hz, respectively, 4, 2, 2, 1, 1 and 2 H, respectively,
r f
8%), m.p. 130–132 °C. t = 23.1. R = 0.61 (hexane/ethyl acetate
ArH) ppm. C NMR: δ = 120.35, 124.10 (q, F
1
3
J
1,2 = 272.2 Hz,
), 124.40, 125.75–125.85 (m, 2 C), 126.75, 127.05, 127.80 (2 C),
31.40 (q, F
1,3 = 32.3 Hz, CCF ), 130.15, 130.30, 130.95, 131.25,
31.80, 133.00, 133.20, 136.00, 142.30, 146.15, 146.90, 155.30 ppm.
:1). 1H NMR: δ = 7.40–7.55 and 7.60–7.65 (2ϫm, 8 and 1 H,
CF
3
3
respectively, ArH), 7.81 (s, 1 H, quinoline H ), 7.84 (d, J = 2.3 Hz,
1
ArH) ppm. C NMR: δ = 119.95, 124.40, 126.40, 127.45 (2 C),
1
1
1
1
J
3
5
H, ArH), 8.13 (s, 1 H, quinoline H ), 8.15–8.20 (m, 2 H,
13
–
1
IR (film): ν˜ = 3053, 1619, 1610, 1583 cm (C=CH). MS: m/z (%)
28.65, 128.75 (2 C), 128.85 (2 C), 129.40 (2 C), 129.50, 130.35,
31.70, 132.15, 137.70, 139.15, 147.15, 148.35, 157.00 ppm. IR
+
=
421 (11) [M + 4] , 420 (20), 419 (66), 418 (57), 417 (100), 416
54), 384 (23), 383 (17), 382 (66), 346 (11), 201 (10), 173 (10).
HRMS calcd. for C22 N: 417.0299; found: 417.0310.
(
–1
(film): ν˜ = 3063, 1593, 1549 cm (C=CH). MS: m/z (%) = 317 (32)
H12Cl F
2 3
+
[M + 2] , 316 (50), 315 (95), 314 (100), 280 (32), 278 (15), 201 (12),
1
39 (18), 139 (20).
r
6-Amino-2,4-diphenylquinoline (3t): Orange oil (0.38 g, 65%), t =
1
3
2.2. R
H, NH
dd, s, m, s, d and m, respectively, J = 2.6, 2.6, 9 and 9 Hz, respec-
f
= 0.17 (hexane/ethyl acetate 4:1). H NMR: δ = 3.90 (s, 2
), 6.95, 7.15, 7.25, 7.40–7.55, 7.70, 8.05 and 8.10–8.15 (d,
6-Chloro-4-phenyl-2-(4-trifluoromethylphenyl)quinoline (3o): Pale
2
yellow solid (0.74 g, 97%), m.p. 141–143 °C. t
r
= 24.8. R
f
= 0.70
1
(hexane/ethyl acetate 4:1). H NMR: δ = 7.45–7.65, 7.70–7.80, 7.85,
1
3
tively, 1, 1, 8, 1, 1 and 2 H, respectively, ArH) ppm. C NMR: δ
105.65, 119.60, 121.40, 127.15 (2 C), 128.05, 128.50 (2 C), 128.65,
28.70 (2 C), 129.40 (2 C), 131.30, 138.95, 139.90 (2 C), 143.85,
44.65, 146.65, 153.40 ppm. IR (film): ν˜ = 3386, 3217 (NH ), 3063,
8
.10 and 8.25 (2ϫm, s and 2ϫd, respectively, J = 9.0 and 8.3 Hz,
=
13
respectively, 6, 3, 1, 1 and 2 H, respectively, ArH) ppm. C NMR:
δ = 119.65, 124.10 (q,
1
1
1
2
2
F
J
1,2 = 272.2 Hz, CF
25.75 (m, 3 C), 126.65, 127.70 (2 C), 128.80 (2 C), 129.35 (2 C),
30.65, 131.20 (q, F
1,3 = 32.9 Hz, CCF ), 131.75, 132.75, 137.40,
42.30, 147.10, 148.75, 155.20 ppm. IR (film): ν˜ = 3069, 1596,
490 cm–1 (C=CH). MS: m/z (%) = 385 (33) [M + 2], 384 (50),
83 (100), 382 (94), 349 (10), 348 (43), 202 (10), 201 (11), 176 (11),
3
), 124.45, 125.60–
2
1
1
1
1
3
1
3
–
1
+
624, 1592, 1551 cm (C=CH). MS: m/z (%) = 297 (23) [M + 1] ,
J
3
96 (100), 295 (52). HRMS calcd. for C21
96.1310.
16 2
H N : 296.1313; found:
+
74 (14), 163 (13), 139 (11). HRMS calcd. for C22
83.0689; found: 383.0685.
3
H13ClF N:
Acknowledgments
-(tert-Butyl)-6-chloro-4-phenylquinoline (3p):[33] Pale yellow oil
This work was supported by the Dirección General de Investiga-
ción (DGI) (Project CTQ2004-01261) of the Spanish Ministerio de
Educación y Ciencia and the Generalitat Valenciana (Project
GV05/157). R. M. thanks the Generalitat Valenciana for a predoc-
toral grant.
2
(
1
0.47 g, 79%), t
NMR: δ = 1.48 [s, 9 H, C(CH
and 8.05 (2ϫd, J = 2.3 and 8.9 Hz, respectively, 1 H each, quino-
r
= 17.9. R
f
= 0.75 (hexane/ethyl acetate 4:1). H
3 3
) ], 7.45–7.60 (m, 7 H, ArH), 7.80
line H5 ) ppm. C NMR: δ = 30.10 (3 C), 38.20, 119.20, 124.20,
,8
13
1
1
1
2
2
25.75, 128.45, 128.70 (2 C), 129.45 (2 C), 29.70, 131.45, 131.50,
38.15, 146.35, 147.45, 169.15 ppm. IR (film): ν˜ = 3066, 1594,
549 cm–1 (C=CH). MS: m/z (%) = 297 (11) [M + 2], 296 (14),
95 (33), 294 (25), 282 (33), 281 (20), 280 (100), 255 (18), 254 (10),
53 (53), 204 (11), 203 (15), 122 (10).
[
1] For reviews on quinoline synthesis see: a) P. A. Claret, Compre-
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+
6-Chloro-4-(2-fluorophenyl)-2-phenylquinoline (3q): White solid
(0.43 g, 65%), m.p. 128–130 °C. t
r
f
= 24.9. R = 0.65 (hexane/ethyl
1
acetate 4:1). H NMR: δ = 7.20–7.30, 7.40–7.50 and 7.60–7.65 (3
1604
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1599–1605

Ru-Catalyzed Solvent-Free Friedländer Synthesis of Quinolines
FULL PAPER
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Received: October 30, 2006
Published Online: February 2, 2007
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Eur. J. Org. Chem. 2007, 1599–1605
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